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PMID: 18927541 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Review

Immunotherapy for advanced melanoma.

The Journal of investigative dermatology ·Vol. 128 ·No. 11 ·2008-11-00 ·Pages 2596-2605

Fang L, Lonsdorf AS, Hwang ST

Abstract

Immunotherapy for melanoma has undergone significant change since the first attempts to treat patients with high dose IL-2. Herein, strategies to boost patient antitumor immunity through vaccination, treatment with agents that augment host immunity, and adoptive cell transfer will be discussed. The first two strategies have yielded only limited clinical success, but adoptive cell transfer therapy, particularly following a lymphodepleting, preconditioning regimen has resulted in objective response rates approaching 50%. For a number of reasons, lymphodepletion appears to be critical for maintenance of circulating antitumor T cells following adoptive cell transfer. Balancing antitumor efficacy, autoimmunity, and reconstitution of a functioning immune system remain challenging and potentially life-threatening issues.

MeSH Terms
Adoptive Transfer/methods Animals CD8-Positive T-Lymphocytes/drug effects,pathology Cancer Vaccines/pharmacology,therapeutic use Disease Models, Animal Humans Immunotherapy/methods Melanoma/immunology,pathology,therapy Mice Skin Neoplasms/immunology,pathology,therapy
Chemicals
Cancer Vaccines
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Fang Lei
Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Lonsdorf Anke S
Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Hwang Sam T
Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: hwangs@mail.nih.gov.
References (98)
98 references, click to expand
  1. Inability to immunize patients with metastatic melanoma using plasmid DNA encoding the gp100 melanoma-melanocyte antigen.
    Hum Gene Ther. 2003 May 20;14(8):709-14 PMID: 12804135
  2. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.
    J Clin Oncol. 2005 Sep 1;23(25):6043-53 PMID: 16087944
  3. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma.
    J Exp Med. 1999 Dec 6;190(11):1669-78 PMID: 10587357
  4. Tumor immunotherapy: preclinical and clinical activity of anti-CTLA4 antibodies.
    Curr Opin Investig Drugs. 2005 Jun;6(6):582-91 PMID: 15988909
  5. Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials.
    Cancer Treat Rev. 2003 Aug;29(4):241-52 PMID: 12927565
  6. Measuring response in a post-RECIST world: from black and white to shades of grey.
    Nat Rev Cancer. 2006 May;6(5):409-14 PMID: 16633367
  7. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.
    J Clin Invest. 2005 Jun;115(6):1616-26 PMID: 15931392
  8. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2.
    JAMA. 1994 Mar 23-30;271(12):907-13 PMID: 8120958
  9. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993.
    J Clin Oncol. 1999 Jul;17(7):2105-16 PMID: 10561265
  10. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells.
    J Exp Med. 2005 Oct 3;202(7):907-12 PMID: 16203864
  11. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells.
    J Exp Med. 1982 Apr 1;155(4):1063-74 PMID: 6460831
  12. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial.
    J Clin Oncol. 2002 Mar 15;20(6):1600-7 PMID: 11896110
  13. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes.
    Science. 2002 Oct 25;298(5594):850-4 PMID: 12242449
  14. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2.
    J Exp Med. 1985 May 1;161(5):1169-88 PMID: 3886826
  15. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma.
    J Clin Oncol. 2005 Apr 1;23(10):2346-57 PMID: 15800326
  16. Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides.
    Curr Oncol Rep. 2004 Mar;6(2):88-95 PMID: 14751085
  17. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells.
    Nat Med. 1998 Mar;4(3):328-32 PMID: 9500607
  18. Update on non-acquired immunodeficiency syndrome-defining malignancies.
    Curr Opin Oncol. 2003 Sep;15(5):389-97 PMID: 12960522
  19. Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine.
    Ann Surg. 1992 Oct;216(4):463-82 PMID: 1417196
  20. Cancer immunotherapy: moving beyond current vaccines.
    Nat Med. 2004 Sep;10(9):909-15 PMID: 15340416
  21. Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells.
    Cancer Res. 2002 Dec 15;62(24):7328-34 PMID: 12499276
  22. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.
    J Clin Oncol. 2006 May 20;24(15):2283-9 PMID: 16710025
  23. Progressive differentiation and selection of the fittest in the immune response.
    Nat Rev Immunol. 2002 Dec;2(12):982-7 PMID: 12461571
  24. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
    N Engl J Med. 2003 Jan 16;348(3):203-13 PMID: 12529460
  25. Topical imiquimod treatment of a cutaneous melanoma metastasis.
    J Am Acad Dermatol. 2000 Sep;43(3):555-6 PMID: 10954675
  26. Immune evasion by murine melanoma mediated through CC chemokine receptor-10.
    J Exp Med. 2003 Nov 3;198(9):1337-47 PMID: 14581607
  27. A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo.
    Nat Biotechnol. 2000 Nov;18(11):1197-202 PMID: 11062441
  28. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b.
    J Clin Oncol. 1999 Mar;17(3):968-75 PMID: 10071291
  29. Adoptive-cell-transfer therapy for the treatment of patients with cancer.
    Nat Rev Cancer. 2003 Sep;3(9):666-75 PMID: 12951585
  30. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation.
    J Exp Med. 1999 Aug 2;190(3):355-66 PMID: 10430624
  31. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206.
    J Clin Oncol. 2005 Dec 10;23(35):8968-77 PMID: 16204013
  32. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer.
    N Engl J Med. 1985 Dec 5;313(23):1485-92 PMID: 3903508
  33. Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon Alfa-2b compared with high-dose interferon Alfa-2b for Resected stage III cutaneous melanoma.
    J Clin Oncol. 2007 May 20;25(15):2078-85 PMID: 17513813
  34. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.
    Nature. 2001 Apr 26;410(6832):1107-11 PMID: 11323675
  35. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684.
    J Clin Oncol. 1996 Jan;14(1):7-17 PMID: 8558223
  36. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer.
    J Immunother. 2005 Nov-Dec;28(6):593-8 PMID: 16224277
  37. Measuring response in solid tumors: unidimensional versus bidimensional measurement.
    J Natl Cancer Inst. 1999 Mar 17;91(6):523-8 PMID: 10088622
  38. Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond.
    Cancer Res. 2007 Apr 15;67(8):3898-903 PMID: 17440104
  39. Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling.
    Cancer Res. 2007 Mar 15;67(6):2425-9 PMID: 17363559
  40. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.
    Nat Immunol. 2005 Apr;6(4):345-52 PMID: 15785760
  41. Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer.
    J Leukoc Biol. 2004 Aug;76(2):333-7 PMID: 15155774
  42. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909.
    J Clin Invest. 2005 Mar;115(3):739-46 PMID: 15696196
  43. T cell homeostatic proliferation elicits effective antitumor autoimmunity.
    J Clin Invest. 2002 Jul;110(2):185-92 PMID: 12122110
  44. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine.
    Cancer Res. 2001 Sep 1;61(17):6451-8 PMID: 11522640
  45. Tumor antigens recognized by T cells.
    Immunol Today. 1997 Jun;18(6):267-8 PMID: 9190110
  46. High efficiency TCR gene transfer into primary human lymphocytes affords avid recognition of melanoma tumor antigen glycoprotein 100 and does not alter the recognition of autologous melanoma antigens.
    J Immunol. 2003 Sep 15;171(6):3287-95 PMID: 12960359
  47. Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1.
    Int J Cancer. 1999 Jan 18;80(2):219-30 PMID: 9935203
  48. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients.
    Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4712-7 PMID: 12682289
  49. Therapeutic vaccines for melanoma: current status.
    BioDrugs. 2005;19(4):247-60 PMID: 16128607
  50. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients.
    J Immunother. 2003 Jul-Aug;26(4):332-42 PMID: 12843795
  51. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens.
    J Natl Cancer Inst. 1998 Dec 16;90(24):1894-900 PMID: 9862627
  52. Successful treatment of malignant melanoma in situ with topical 5% imiquimod cream.
    Int J Dermatol. 2005 May;44(5):428-34 PMID: 15869545
  53. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8372-7 PMID: 12826605
  54. Density of DC-LAMP(+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor.
    Cancer Immunol Immunother. 2007 Sep;56(9):1459-69 PMID: 17279413
  55. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.
    Ann Surg Oncol. 2005 Dec;12(12):1005-16 PMID: 16283570
  56. Adoptive transfer of vaccine-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion.
    J Immunol. 2006 Nov 1;177(9):6527-39 PMID: 17056585
  57. High frequencies of naive Melan-A/MART-1-specific CD8(+) T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals.
    J Exp Med. 1999 Sep 6;190(5):705-15 PMID: 10477554
  58. Specificity of adoptive chemoimmunotherapy of established syngeneic tumors.
    J Immunol. 1980 Aug;125(2):711-4 PMID: 6156213
  59. Adoptive therapy with CD8(+) T cells: it may get by with a little help from its friends.
    J Clin Invest. 2002 Nov;110(10):1415-7 PMID: 12438439
  60. Adoptive immunotherapy for cancer: building on success.
    Nat Rev Immunol. 2006 May;6(5):383-93 PMID: 16622476
  61. Active specific immunotherapy for melanoma: phase I trial of allogeneic lysates and a novel adjuvant.
    Cancer Res. 1988 Oct 15;48(20):5883-93 PMID: 3262416
  62. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance.
    Cancer Res. 2004 Apr 15;64(8):2865-73 PMID: 15087405
  63. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer.
    Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18538-43 PMID: 16344461
  64. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells.
    Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73 PMID: 12427970
  65. Tolerance, not immunity, crucially depends on IL-2.
    Nat Rev Immunol. 2004 Sep;4(9):665-74 PMID: 15343366
  66. Improved long-term survival after lymphadenectomy of melanoma metastatic to regional nodes. Analysis of prognostic factors in 1134 patients from the John Wayne Cancer Clinic.
    Ann Surg. 1991 Oct;214(4):491-9; discussion 499-501 PMID: 1953101
  67. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling.
    J Clin Invest. 2007 Aug;117(8):2197-204 PMID: 17657310
  68. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
    Nat Med. 2004 Sep;10(9):942-9 PMID: 15322536
  69. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group.
    J Clin Oncol. 2002 Apr 15;20(8):2058-66 PMID: 11956266
  70. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells.
    J Immunol. 2004 Jul 15;173(2):1444-53 PMID: 15240741
  71. Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group.
    J Clin Oncol. 2005 Sep 20;23(27):6747-55 PMID: 16170182
  72. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients.
    Nat Med. 1999 Jun;5(6):677-85 PMID: 10371507
  73. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2.
    J Natl Cancer Inst. 1994 Aug 3;86(15):1159-66 PMID: 8028037
  74. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells.
    Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1969-74 PMID: 14762166
  75. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation.
    J Exp Med. 2000 Aug 21;192(4):557-64 PMID: 10952725
  76. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG.
    Ann Oncol. 2006 Apr;17(4):563-70 PMID: 16418308
  77. Intratumor CpG-oligodeoxynucleotide injection induces protective antitumor T cell immunity.
    J Immunol. 2003 Oct 15;171(8):3941-6 PMID: 14530311
  78. Prolonged survival after complete resection of disseminated melanoma and active immunotherapy with a therapeutic cancer vaccine.
    J Clin Oncol. 2002 Dec 1;20(23):4549-54 PMID: 12454111
  79. Dendritic cells as initiators of tumor immune responses: a possible strategy for tumor immunotherapy?
    Immunol Today. 1995 Mar;16(3):117-21 PMID: 7718082
  80. Chemokines, chemokine receptors, and cancer metastasis.
    J Leukoc Biol. 2006 Apr;79(4):639-51 PMID: 16478915
  81. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma.
    J Immunother. 2002 May-Jun;25(3):243-51 PMID: 12000866
  82. A molecular perspective of CTLA-4 function.
    Annu Rev Immunol. 2006;24:65-97 PMID: 16551244
  83. Transduction of an IL-2 gene into human melanoma-reactive lymphocytes results in their continued growth in the absence of exogenous IL-2 and maintenance of specific antitumor activity.
    J Immunol. 2001 Dec 1;167(11):6356-65 PMID: 11714800
  84. Cancer regression in patients after transfer of genetically engineered lymphocytes.
    Science. 2006 Oct 6;314(5796):126-9 PMID: 16946036
  85. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients.
    Blood. 2006 Mar 15;107(6):2409-14 PMID: 16304057
  86. Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent.
    Arch Dermatol. 2006 Feb;142(2):166-72 PMID: 16490844
  87. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190.
    J Clin Oncol. 2000 Jun;18(12):2444-58 PMID: 10856105
  88. Sensitization of B16 tumor cells with a CXCR4 antagonist increases the efficacy of immunotherapy for established lung metastases.
    Mol Cancer Ther. 2006 Oct;5(10):2592-9 PMID: 17041104
  89. Phase 1/2 study of subcutaneous and intradermal immunization with a recombinant MAGE-3 protein in patients with detectable metastatic melanoma.
    Int J Cancer. 2005 Nov 20;117(4):596-604 PMID: 15945101
  90. Involvement of chemokine receptors in breast cancer metastasis.
    Nature. 2001 Mar 1;410(6824):50-6 PMID: 11242036
  91. Perspective on allogeneic melanoma lysates in active specific immunotherapy.
    Semin Oncol. 1998 Dec;25(6):623-35 PMID: 9865677
  92. Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells.
    J Clin Oncol. 2003 Nov 1;21(21):4016-26 PMID: 14581425
  93. Phase II study of temozolomide plus pegylated interferon-alpha-2b for metastatic melanoma.
    Cancer. 2006 Jun 1;106(11):2445-51 PMID: 16639739
  94. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells.
    J Exp Med. 2002 Jun 17;195(12):1523-32 PMID: 12070280
  95. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma.
    Nat Med. 1998 Mar;4(3):321-7 PMID: 9500606
  96. Inhibition of growth of B16 murine malignant melanoma by exogenous interferon.
    Cancer Res. 1980 Mar;40(3):614-9 PMID: 6162552
  97. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells.
    J Immunol. 2005 Mar 1;174(5):2591-601 PMID: 15728465
  98. Enhancement of antitumor immunity by CTLA-4 blockade.
    Science. 1996 Mar 22;271(5256):1734-6 PMID: 8596936
Article Info
Journal
The Journal of investigative dermatology
Abbr.
J Invest Dermatol
ISSN
1523-1747
DOI
10.1038/jid.2008.101
Email
hwangs@mail.nih.gov
Published
2008-11-00
Pages
2596-2605
Language
English
Region
United States
NLM ID
0426720
PMCID
PMC6953395
Subset
IM
Grants
Intramural NIH HHS · Z01 BC010924 · United States
External Links
PubMed source DOI: 10.1038/jid.2008.101 PMC Full Text View journal details
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